"The universe is full of magical things, patiently waiting for our wits to grow sharper." — Eden Phillpotts.

Saturday, February 26, 2005

Is Avian Influenza THAT deadly?

Avian Influenza type A subtype H5N1 that is currently found in southeast Asia shows the potential to develop into another deadly influenza pandemic. Already, two of the three criteria that characterized the influenza pandemic of 1918-1919 have been fulfilled by the current epidemic of avian influenza: (1) the ability of the virus to infect humans and cause high mortality and (2) the presence of an immunologically naive human population around the globe. The third criterion, efficient human-to-human transmission, has not yet been officially reported.

But the reported mortality rate for H5N1, which is estimated to be somewhere between 35-70%, raises important questions about how such things are calculated. For example, the World Health Organization (WHO) Web site reports that the H5N1 mortality rate was greater than 70% among persons with recognized cases in 2004. WHO officials conservatively estimate that H5N1 could infect up to 30% of the world’s population and kill between 2 and 7 million people.

“The maximum range is more ... maybe 20 to 50 million people,” said Shigeru Omi, regional director of WHO’s Western Pacific Regional Office, in a speech in Hong Kong in late 2004. Given these data, everyone agrees that if an H5N1 pandemic occurs, it will be an international disaster.

But an article published yesterday in the journal, Nature (Vol. 433, page 787, Thursday 24 Feb 2005), claims that human cases of Avian Influenza have been under-diagnosed and possibly misdiagnosed. This paper reports that re-testing by several independent labs of samples collected from Vietnamese patients showing flu-like symptoms reveal that more people test positive for infection with the “Bird Flu” than previously thought. This new data has several effects.

First, this reveals that Avian Influenza is probably more widespread in the human population than originally thought. This is a public health concern because every new human infection presents the virus with additional opportunities to mutate into a more infectious and deadly form. But the Nature paper also mentions that preliminary genetic analyses at the National Institute of Infectious Diseases (NIID) in Tokyo show that Avian Influenza has not changed much in one year. This is fortunate, especially considering that the influenza virus is adept at both generating mutations and undergoing dramatic genomic rearrangements -- both serve to potentially increase its infectivity and virulence.

Re-testing of these samples has also directed health officials’ attention to the unusual symptoms of some Avian Influenza patients. Instead of showing the typical respiratory symptoms associated with influenza, one patient who was infected with H5N1, for example, developed encephalitis (swelling of the brain). Since encephalitis is common in Viet Nam, this development raises concerns that identification of influenza patients might become much more difficult and labor-intensive. But so far, it appears that this case is unique: 100 additional encephalitis patients tested negative for Avian Influenza.

The new data generated by re-testing of existing samples give us a better picture of the nature of H5N1 and also mean that at least some of the calculated mortality rates for this virus are probably excessively high. For example, the Nature paper states that 10 out of 11 identified cases of Avian Influenza in Viet Nam since December 2004 have died (now; 13 out of 18). This is a mortality rate of 91% (or 72% using the more recent data)! Given these statistics, it’s no wonder that public health officials around the world are in a panic.

But because doctors, labs and hospitals have focused their attention on the most severe cases, less severe H5N1 cases have been ignored, and this (obviously) skews mortality data as well as our understanding of the virus’s infectivity -- both are important for assessing Avian Influenza’s potential for damage. Currently, officials are trying to address this situation by conducting a one-year survey of 1600 children with mild flu-like symptoms in Viet Nam to identify H5N1. Additionally, NIID has already discovered 7 more “positives” for H5N1 among those samples that previously tested negative: These data resulted after retesting only one third of 90 suspected Vietnamese cases of Avian Influenza thus far. Not only does this difficulty of identifying H5N1 alter our calculated infectivity and mortality statistics but it also interferes with officials’ efforts to identify and monitor possible instances of human-to-human transmission -- the last criterion that must be met before an effective pandemic of H5N1 can occur.

These “false negatives” produced by Vietnamese labs also indicated problems with either the test used or the training that lab technicians received, or both. [Unfortunately, the article never reveals the nature of test is being used to identify people who had an infection with influenza, but this information is also critically important to making an accurate assessment of the transmissibility and infectivity of the virus (and therefore, its virulence), as well as making it easier to identify the virus by its symptoms.] Nevertheless, after further investigation, Vietnamese officials are switching to the more sensitive test used by the NIID labs in Tokyo and they are also providing more rigorous training to their lab workers.

As reported by the referenced article in Nature, the bad news is that H5N1 appears to be more widespread than realized, it can trigger unusual symptoms that make it difficult to identify, and it might already be exhibiting limited person-to-person transmission in crowded situations. Currently, health officials do not yet know the true infectivity or mortality of Avian Influenza in humans, but epidemiologists are working to answer those questions. Even though H5N1 is dangerous because of its potential to enter the human population and then become more deadly should not be underestimated, the good news is that the current form of H5N1 probably has a lower mortality rate than previously thought. Although the referenced article never actually highlights this, I think this is very good news in our fight to contain the spread of Avian Influenza.

My brain, which collects all sorts of information from the many (many!) papers, books and magazines that I read, from the scientists who tell me cool things, and from the superb university classes I've taken.

Interesting, but I don't understand your last line.If the mortality is lower than previously reportedthat's certainly good news. Infecting a third ofthe world's population and killing more than half of them would mean more than a billiondeaths! However, this has nothing to do with controling the spread of the virus, and from thatpoint of view it looks like bad news. Mild casesare harder to track, especially in countries withhigh disease rates.

Currently, person-to-person transmission of Avian Influenza is really inefficient, although it is probably happening. This alone is worthy of great concern, in my opinion, BUT that said, the virus is (so far) not as deadly as first suspected.

Since the world health officials' primary strategy has changed from eradication (a futile exercise because it was already a lost cause by the time they started, in my opinion) to containment, this (probable) decreased mortality rate is good news. However, I do not want my comments to make it seem that I am "making light" of the situation because I am not. I am instead presenting a "cup half full" scenario: Hopefully, enough local people will build up an immunity (due to subclinical infections or vaccination) to the virus such that it cannot easily escape to rampage across the globe because it is contained by this "ring of immunity" in the nearby human community.

I am aware that other, less favorable, scenarios are possible. I will explore those possibilities in articles I am working on now.

Two comments;1) clearly there is a great deal of mystery surrounding mortality rates. The WHO estimate is clearly a typical 0.1-0.3% rate (about 1/1000 out of 1.8 billion or so yields ~2 million). There are many interesting facets to it, and I would recommend to anyone who hasn't read it the book by John Barrie "The Great Influenza" (IIRC), which describes the 1918-1919 pandemic in at times excruciating detail. The most interesting issue, I suspect, will be the nature of the virus' effect on people outside the typical susceptible group (in other words, young healthy adults). The 1918-1919 pandemic bug caused a frighteningly severe primary influenza, which often resulted in death without a secondary pneumonia.2) Worldwide public health, social, and environmental factors will certainly play a role in the spread of any new pandemic- the role of army camps and trench warfare in the incubation and spread of pandemic flu is well known. It is not clear that even a new, highly virulent, highly transmissible influenza would have similar effects in today's world. Of course, this is no reason to be complacent! It just means that we should think hard about other possible signals of pandemic influenza, especially in terms of epidemiological surveillance.

Thanks for your comments, paul and for the book recommendation! I have long wanted to get that book but have not yet been able to afford it (since this book is about disease, it's on my "purchase" list rather than my "borrow from the library" list).

This is indeed possible, Dr. Andy, but influenza pandemics start out as relatively innocuous infections (very painful but not very lethal) but after a 1-2 years, the virus increases its lethality and transmissability to truly astonishing levels. This process is called "passage" by microbiologists and virologists, and it appears to be typical of the flu virus. For example, the book, America's Forgotten Pandemic [Alfred W. Crosby, 1989, ISBN: 0521386950] states "the onset of illness for the individual patient was very sudden, the passage from health to near prostration taking only one to two hours."